This is a very opportune time to study the genetic basis of complex phenotypes such as susceptibility to cancer. There are undoubtedly many genes that contribute to this phenotype and discovering their identities should lead to advances in cancer diagnosis, prevention, and even treatment. The mouse has always been the best experimental system for genetic analysis of complex mammalian traits, and with the sequencing of the mouse genome the utility of mouse models for identification of the genes at cancer susceptibility/resistance loci is further enhanced. Using a transgenic mouse model, we have previously demonstrated that the ornithine decarboxylase (Ode) gene is a susceptibility gene for nonmelanoma skin cancer in the mouse. When Odc is overexpressed in the target cells for carcinogens in skin, a previously resistant mouse strain becomes highly sensitive to skin tumorigenesis. Despite the strong effect of Odc on susceptibility, this phenotype can be modified by genetic loci present in a variety of inbred mouse strains. Published and ongoing genetic mapping studies have identified two classes of modifier loci, those that affect total tumor multiplicity and those that affect predisposition to squamous cell carcinoma development. The genes present at these loci presumably function in important effector pathways that: (a) are relevant to the tumor development process and (b) sensitive to changes in intracellular polyamine levels caused by Odc overexpression. In this proposal, we will focus our attention on fine mapping of these modifier loci, identifying the genes at these loci, and developing new models to study the genes' function in vivo. The specific objectives are to: (1) Fine map and identify the gene at Moo1 a strong modifier of tumor multiplicity on chromosome 17; (2) Map an X-linked modifier locus in crosses involving the C57BL/6J and BALB/cJ strains; (3) Fine map and identify the gene at Moo2, a strong modifier of tumor multiplicity on chromosome 6; (4) Develop novel mouse models in which an important regulatory region of the human ODC gene is knocked in to the homologous region of the mouse gene. Common allelic variants of modifier genes undoubtedly contribute greatly to the differences between individuals in human cancer susceptibility. Identifying such genes through research on human populations is extremely difficult, but utilizing genetic analysis in the mouse to identify mouse modifier genes is now quite feasible. In the very near future, it should be possible to test hypotheses about human cancer modifier genes using results derived from mouse models.